tbuckley/cabot-search huggingface dataset:
Antitumor activity of intraperitoneal (IP) paclitaxel to mucinous appendiceal adenocarcinoma in orthotopic patient-derived xenograft model.
Authors: Ichiaki Ito, Abdelrahman M.G. Yousef, Princess A Dickson, Keith F. Fournier, Natalie Wall Fowlkes, John Paul Y.C. Shen
Journal: Journal of Clinical Oncology (2023)

151 Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which only few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy like those for colorectal cancer despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. Taxanes such as paclitaxel (PTX) and docetaxel have been used in the systemic treatment of gastric cancer with peritoneal metastases. IP administration of PTX has been considered a promising treatment for eliminating peritoneal metastasis, as IP delivery of PTX can attain a higher drug exposure in the peritoneal cavity with reduced systemic toxicity because of high local concentrations over a long period of time due to its hydrophobic property. The purpose of this study was to test the efficacy of IP PTX treatment in orthotopic AA PDX models. Methods: AA tumors TM00351, PMP-2 and PMCA-3 were implanted in the peritoneal cavity of NSG mice. PDX models were treated with PTX (6.25, 12.5 or 25.0 mg/kg, IP) with weekly (3 weekly treatments and 1 week off, for two cycles) or biweekly (biweekly treatments for up to 12 weeks) schedule. The peritoneal tumor burden was monitored by MRI. Solid tumor size was evaluated by modified peritoneal Response Evaluation Criteria In Solid Tumors (mpRECIST) method using ImageJ software and mucinous tumor volume was quantified by OsiriX Lite software. Results: TM00351, taken from a high-grade tumor (Grade 3), formed mucin-rich solid tumors with mucinous ascites. PDX models PMP-2 (Grade 2) and PMCA-3 (Grade 3), both with GNASR201C mutation, had a mucinous phenotype similar to GNAS mutant appendiceal tumors in humans. Weekly 25.0 mg/kg of IP PTX treatment reduced AA tumor growth of TM00351 (77.9% reduction vs. control), PMP-2 (98.6% reduction vs. control), and PMCA-3 (85.6% reduction vs. control). Similarly, biweekly 25.0 mg/kg of IP PTX treatment was effective on PMCA-3 (66.2% reduction vs. control). Survival of PMCA-3 PDX mice was significantly improved by 12.5 mg/kg (p=0.0254, log-rank test) and 25.0 mg/kg (p=0.0038) of IP PTX. At 25.0 mg/kg IP PTX treatment induced 12.0% body weight loss of PMCA-3 PDX mice 1 week after the treatment. Lower doses of IP PTX treatment, 6.25 and 12.5 mg/kg, did not induce significant body weight loss or any noticeable adverse effects on mice. Comparing the efficacy of IV to IP administration, neither 6.25 or 12.5 mg/kg of IV PTX reduced growth of PMCA-3, 25.0 mg/kg of IV PTX was lethal to mice shortly after administration. Conclusions: IP PTX is a therapeutically active for mucinous AA tumors.
Phase 1 trial of the anti-LAG3 antibody favezelimab plus pembrolizumab in advanced gastric cancer.
Authors: Sun Young Rha, Wilson H. Miller, María José de Miguel, Seock-Ah Im, Iwona Lugowska, Martin Wermke, Daisuke Kotani, Todd Michael Bauer, Atsuo Takashima, John Palcza, Marya F. Chaney, Konstantin Dobrenkov, Elena Garralda
Journal: Journal of Clinical Oncology (2023)

394 Background: In the dose-confirmation phase of this multicohort trial (NCT02720068), the anti-LAG-3 antibody favezelimab had a manageable safety profile and promising antitumor activity in patients (pts) with advanced solid tumors, confirming preliminary RP2D. Here we present results on the safety of favezelimab (fave) plus pembrolizumab (pembro) in all treated pts and efficacy in pts with advanced gastric cancer. Methods: In this phase 1b trial eligible pts aged ≥ 18 years were enrolled into 7 cohorts across 3 tumor types: Cohorts A (3L+ CRC), B (1L/2L CRC), C (PD-1 naïve HNSCC), D (PD-1 refractory HNSCC), E (PD-1 naïve gastric cancer), F (all solid tumors), and G (PD-1 naïve 3L CRC). Pts with gastric cancer in cohort E received either 200 mg fave + 200 mg pembro, or 700 mg fave + 200 mg pembro Q3W up to 35 cycles. Treatment continued until progression, unacceptable toxicity, or pt withdrawal. Primary endpoint was safety and tolerability of fave + pembro. Secondary endpoint was ORR per RECIST 1.1 by investigator assessment. Exploratory endpoints were PFS per RECIST 1.1, and OS. Data cutoff date was March 21, 2022. Results: At data cutoff, 397 pts were enrolled: 38 to fave, 368 to fave + pembro including 9 who crossed over from fave alone. Of these, 80 pts had gastric cancer; 50 (62.5%) of which had ≥2 lines of treatment, and 48 (60.0%) had PD-L1 CPS≥ 1. Among 368 pts treated with fave + pembro, treatment-related adverse events (TRAEs) occurred in 232 (63.0%) with fave + pembro. Grade ≥3 TRAEs occurred in 66 (17.9%) pts with fave + pembro. There were no grade 5 TRAEs. Immune-mediated adverse events (AEs) occurred in 121 (32.9%) pts with fave + pembro. Grade ≥3 immune-mediated AEs occurred in 27 (7.3%) pts with fave + pembro. No grade 5 immune-mediated AEs occurred. In pts with gastric cancer, the overall ORR was 11.3% (95% CI, 5.3-20.3 [3.8% CR; 7.5% PR]) with fave + pembro. In 2 arms, higher dose of fave (700mg) showed increased ORR and 12 months PFS rate. The table summarizes antitumor activity in the gastric cancer cohort. Conclusions: Favezelimab alone or in combination with pembrolizumab had an acceptable safety profile. The combination therapy showed antitumor activity in line with other checkpoint inhibitors in advanced gastric cancer though higher antitumor activity was seen in PDL1 CPS≥ 1 tumors, particularly at higher dose. Clinical trial information: NCT02720068 . [Table: see text]
Use of distinct molecular signatures of appendiceal cancer subtypes to assess biomarker development.
Authors: Wan Ying Tan, Melissa Tian, Nensi Ruzgar, Astrid Hengartner, Bethsebie Sailo, Olivia Ang-Olson, Airol Ubas, Nithyla John, Vesal Yaghoobi, Haoyu Tang, Anup Sharma, ILKe Nalbantoglu, Nita Ahuja
Journal: Journal of Clinical Oncology (2023)

189 Background: Appendiceal Neoplasms are diverse entities which have a variety of clinical presentations, histologic subtypes, biologic behavior, and patient outcomes. Advanced disease at initial diagnosis is not uncommon and therapeutic options are limited. This study aims to identify potential targets to develop epigenetics-based therapeutics/biomarkers. Methods: Archival (FFPE) specimens were collected from 25 patients with histologically confirmed and subtyped appendiceal neoplasia and 16 age-matched non-neoplastic controls. Four appendiceal neoplastic processes identified: Low grade appendiceal neoplasm (LAMN), pseudomyxoma peritonei (intra-peritoneal spread of LAMN), conventional-type adenocarcinoma and goblet cell adenocarcinoma. Gene expression profiling was performed using the HTG EdgeSeq Oncology Biomarker panel. Differentially expressed genes (DEGs) were selected with cut-off threshold FDR&lt;0.05 and analyzed using Qlucore Explorer and functional analyses via Ingenuity Pathway Analysis (IPA). Results: Four appendiceal neoplastic processes identified: pseudomyxoma peritonei (20%), low-grade appendiceal mucinous neoplasm (24%), adenocarcinoma (24%), and goblet cell adenocarcinoma (32%). Unsupervised hierarchical clustering identified 498 DEGs (424 up, 74 down) between all appendiceal cancer versus age-matched controls that showed enrichment in B-cell inflammatory signaling, senescence, cell cycle regulation, PI3K/AKT signaling, cell cycle checkpoint control pathways, and sets relating to NANOG in stem cell pluripotency (all p0.001). G1/S checkpoint, apoptosis, ATM, and PTEN signaling are downregulated (p0.001). TP53, E2F1, IL6, IFNG, TNF, and HGF (p0.001) regulated overlapping genes. Four-subgroups comparison found 67 DEGs involved in T-helper cell differentiation, immune-mediated apoptosis, T-cell fatigue, and PD1/PDL1 signaling to be dysregulated (p0.001). IFNG, FGF2, POU5F1, TNF, and MYC (p0.001) were upstream regulators. Conclusions: In this study, downregulated gene expressions in appendiceal cancers are related to cell proliferation and death control mechanisms, with a trend towards overexpression of inflammatory and cell cycle pathways. It is postulated that genes involved in these pathways are hypermethylated. More research is being undertaken on epigenetics-based biomarkers for diagnosis and prognosis. Given PI’s decades of experience in biomarker research, we aim to develop a "single blood test" to expand bedside monitoring alternatives that align with the National Cancer Moonshot Initiative to discover cancer early, when the likelihood of a cure is highest.
Use of FOLFOXIRI plus bevacizumab in metastatic colorectal cancer (mCRC): An age-stratified analysis.
Authors: Zdravko Vassilev, Xiaozhou Fan, Helene Ostojic, Julie Xu, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2023)

64 Background: As the incidence of early-onset mCRC continues to rise, evidence is emerging for the use of more aggressive treatment in the front-line setting in patients aged &lt; 50 years (yrs). Although the superior efficacy of the multiagent chemotherapy FOLFOXIRI+bevacizumab (triplet+bev) over doublet regimens (FOLFOX or FOLFIRI+bev) is well documented, it is commonly associated with increased toxicity. Contemporary data are needed on triplet+bev use by age group in the US, which may help tailor treatment in patients with early-onset mCRC. Methods: This was a retrospective, observational cohort study using Optum Oncology Electronic Health Records data between 2010 and 2021. Use of triplet+bev and subsequent treatments were reported by age group (18–49, 50–64, ≥65 yrs) among newly diagnosed patients with mCRC. Baseline demographic and clinical characteristics data for patients receiving triplet+bev and regorafenib as a subsequent treatment were collected. Results: Among 36,053 eligible patients with mCRC diagnosed between 2010 and 2021, 13.8% were aged 18–49 yrs, 36.4% 50–64 yrs, and 49.8% ≥65 yrs at the time of diagnosis. The proportion of patients receiving triplet+bev was higher in age groups 18–49 yrs (4.0%) and 50–64 yrs (3.4%) vs ≥65 yrs (1.5%). Between 2010 and 2020, the proportion of patients receiving triplet+bev changed from 1.5% to 4.2% in age group 18–49 yrs, from 3.1% to 2.6% in 50–64 yrs, and from 1.1% to 1.2% in ≥65 yrs. Over a median 20-month follow-up period, 58.0% of patients in age groups 18–49 and 50–64 yrs, and 53.7% of patients in age group ≥65 yrs, received a new treatment after triplet+bev. In the overall cohort, the most common new treatment after triplet+bev was regorafenib (20.7%), received by 18.2% of patients in age group 18–49 yrs, 22.7% in 50–64 yrs, and 19.2% in ≥65 yrs. Other new subsequent treatments in the overall cohort included trifluridine/tipiracil (17.1%) and cetuximab (16.3%), with a similar trend seen among all age groups. Across age groups, triplet+bev recipients were more likely to be male, obese, resident in the Midwest or Northeast, and have distant metastases, and less likely to have colorectal surgical resection prior to mCRC diagnosis. Patients in age group 18–49 yrs subsequently receiving regorafenib were more likely to be obese and less likely to have Charlson Comorbidity Index ≥3, distant metastases, and colorectal surgical resection before mCRC diagnosis vs those who did not receive regorafenib. Conclusions: Our study shows that, recently, triplet+bev use has increased in patients with mCRC, particularly in those aged &lt; 50 yrs. Chemotherapy-free treatments may be an option for these patients beyond the first-line setting. While regorafenib is typically used in third or later lines, these real-world data suggest it is often a preferred option following triplet+bev treatment.
Phase 1/2 trial of vesicular stomatitis virus expressing human interferon-β and NIS (VSV-IFNβ-NIS), with pembrolizumab, in patients with neuroendocrine carcinoma.
Authors: Patrick Walsh McGarrah, Shruthi Naik, Thorvardur Ragnar Halfdanarson, Konstantinos Leventakos, Kah Whye Peng, Stephen J. Russell, Alex A. Adjei, Julian R. Molina
Journal: Journal of Clinical Oncology (2023)

TPS657 Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of single agent immune checkpoint inhibitors (ICIs) in NEC has been disappointing. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety of VSV-IFNβ-NIS in combination with a single agent ICI, pembrolizumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. The safety run-in portion of this study has been completed, and we are presently testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated one time with the RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 1, followed by pembrolizumab on day 8 and then pembrolizumab every 21 days until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .
Enhancing nanoparticle paclitaxel antitumor response through targeted inhibition of c-Met pathway by merestinib in gastric cancer models.
Authors: Quinn Kaurich, Jennifer Huang, Niranjan Awasthi
Journal: Journal of Clinical Oncology (2023)

372 Background: Gastric adenocarcinoma (GAC) is the fifth most common malignancy and the third most common cause of cancer-related deaths worldwide. Combination chemotherapy regimens are commonly used to treat GAC, but the median survival time remains less than one year. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT), an approved treatment for breast cancer, non-small cell lung cancer and pancreatic cancer, has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. Aberrant activation of the c-Met pathway has been reported in up to 50% of GAC patients. We hypothesize that merestinib, a small-molecule inhibitor of c-Met, with additional inhibition of Axl and DDR1/2 pathways, will have significant antitumor effects and will enhance nab-paclitaxel chemotherapy response in GAC preclinical models. Methods: GAC subcutaneous xenografts were established by injecting MKN-45 and SNU-1 cells in NOD/SCID mice to study treatment effects on tumor volume, tumor weight, net tumor growth, and mouse body weight. Immunohistochemistry analyses of xenograft tissues were performed using Ki67 and endomucin to examine tumor cell proliferation and microvessel density, respectively. Results: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three GAC-associated cell lines tested, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of pro-apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased pro-apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab-paclitaxel, merestinib, and combination groups was 503 mm 3 , 115 mm 3 , 91 mm 3 , and -9.7 mm 3 . Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results. Conclusions: These findings suggest that merestinib has strong antitumor activity in GAC and exhibits an additive effect when administered with nab-paclitaxel. These results provide compelling evidence that this therapeutic approach may lead to a clinically relevant combination to improve GAC patients’ survival.
Circulating tumor DNA (ctDNA) dynamics and clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) undergoing front-line chemotherapy.
Authors: Michele Ghidini, Jens Claus Hahne, Chiara Senti, Gianluca Tomasello, Margherita Ratti, Timon Heide, Ornella Garrone, Alessio Cortellini, Rodolfo Passalacqua, Nicola Valeri
Journal: Journal of Clinical Oncology (2023)

175 Background: The potential of monitoring circulating tumor DNA (ctDNA) dynamics to guide clinical decisions in metastatic colorectal cancer (mCRC) patients (pts) treated with I and II line systemic anti-cancer therapy (SACT) has not been widely tested. Methods: 862 serial plasmas were collected 4-weekly from baseline (BL) until disease progression in 75 mCRC pts undergoing SACT. ctDNA was tested using a custom (RMH GI; 20 genes) or a commercial (Roche Avenio; 77 genes) ctDNA next generation sequencing (NGS) panel. White blood cells were sequenced to rule out clonal hematopoiesis. Whole exome sequencing (WES) was performed on tissue biopsies. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA. Results: 83 paired samples from 75 pts were available for analysis (for 8 pts, I and II line bloods were available). 12 pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 pts), 37 (52.1%) showed ctDNA normalization at Mo1. Among normalized pts there was a higher proportion of cases with a baseline ECOG performance status (PS) 0-1 (97.3% vs 82.4%, p = 0.0362) in comparison to non-normalized pts, whilst no other clinic-pathologic characteristics, including age, sex, prior primary tumor resection, sidedness, RAS/RAF genotype, type of regimen and number of metastatic sites were significantly associated with ctDNA dynamics. Pts with normalized ctDNA had significantly longer overall survival (OS), 45.6 months (95% confidence interval [CI]: 30.0 - not reached, 14 events) and progression-free survival (PFS), 13.9 months (95%CI: 11.2-18.3; 30 events) compared to non-normalized pts [OS = 22.6 months (95%CI: 16.6-31.2, 24 events) (Log-rank p = 0.01) and PFS = 10.7 months (95%CI: 7.53-13.8; 32 events) (Log-rank p = 0.036) respectively]. In addition, pts with normalized ctDNA had higher overall response rate (ORR) of 72.9% (27/37 responses; 95%CI: 53.0-84.1) compared to 38.2% (13/34 responses; 95%CI: 22.1 – 56.4) in non-normalized pts. In a multivariate model, ctDNA normalization was confirmed as an independent predictor of decreased risk of death (hazard ratio [HR] 0.47, 95%CI: 0.23-0.96; p = 0.04) and higher probability of achieving an objective response from front-line treatment (odds ratio [OR] 3.03, 95%CI: 1.08-8.49; p = 0.0351). Only 23/50 (46%) of variants detected in ctDNA were detected by WES in paired tissues in 12 pts for whom liquid/solid biopsy was available. Conclusions: ctDNA monitoring represents an early indicator of benefit from systemic therapy in mCRC pts. A significant fraction of variants detected in ctDNA was not detected in paired tissues.
The mortality burden of cachexia in patients with colorectal or pancreatic cancer: A systematic literature review.
Authors: Richard Francis Dunne, Philip D. Bonomi, Jeffrey Crawford, Karen E Smoyer, Thomas D McRae, Michelle I Rossulek, James H Revkin, Lisa C Tarasenko
Journal: Journal of Clinical Oncology (2023)

87 Background: Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (WL, skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer. Methods: The SLR was conducted following PRISMA guidelines. Embase and PubMed were searched to identify articles published in English between 1 Jan 2016 and 10 Oct 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by International Consensus (IC) diagnostic criteria (Fearon et al., Lancet Oncol 2011;12:489–95) or a broader definition of any WL. Included publications were of studies in ≥100 patients with colorectal or pancreatic cancer. Results: Twenty-six publications in patients with colorectal (n=13) or pancreatic cancer (n=13) met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 studies (58%) reported any WL. An association between survival and cachexia/WL was assessed across studies using multivariate (n=23) or univariate (n=3) analyses and within each study across multiple WL categories. Cachexia/WL was associated with a statistically significantly poorer survival in at least one WL category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Conclusions: Cachexia/WL was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of WL varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could inform early disease management strategies that may improve prognosis.